Antiviral c-nucleoside derivatives

ABSTRACT

The present invention is composed of a nucleoside derivative of the following general formula  I!: ##STR1## (wherein B represents adenin-9-ylmethyl, guanin-9-ylmethyl, hypoxanthin-9-ylmethyl, thymin-1-ylmethyl, uracil-1-ylmethyl, or cytosin-1-ylmethyl; X and Y may be the same or different and each represents hydrogen or hydroxy, exclusive of the case in which X is hydrogen and Y is hydroxy). 
     The compound of the present invention is useful as an antiviral agent or an antimalignant-tumoral agent.

This application is a 371 of PCT/JP 94/02059 filed Dec. 12, 1994.

TECHNICAL FIELD

The present invention relates to a novel nucleoside derivative havingantiviral or antimalignant-tumoral activities.

BACKGROUND TECHNOLOGY

Being transmitters of genetic information in living matter, nucleicacids play a crucial role in the differentiation and growth of cells.Among natural and unnatural nucleoside derivatives, many derivatives areknown to inhibit biosynthesis of nucleic acids and are, therefore,useful as antiviral or antimalignant-tumoral agents. As antiviralagents, for instance, vidarabine (Ara-A: C. R. Acad. Soc. D (Paris),259, 2725 (1964)), acyclovir (Proc. Natl. Acad. Sci, USA, 74, 5716(1977)), azidothymidine (Proc. Natl. Acad. Sci, USA, 82, 7096 (1985)),2',3'-dideoxyinosine (DDI), 2',3'-dideoxycytidine (DDC: WO90/14079),among other nucleosides, are known. As antimalignant-tumoral agents,cytarabine (Ara-C), enocitabine, thioinosine, etc. are known.

However, none of the above-mentioned antiviral agents andantimalignant-tumoral agents are fully satisfactory from the standpointof effects and adverse actions. It is guessed to be one of the causesfor insufficient efficacy that the above-mentioned nucleosidederivatives have the chemical structure in which the nucleic acid basemoiety is directly bound to the sugar one and, therefore, they aresusceptible to hydrolysis by acid or alkali and the nucleosidederivatives with activity are ready to be metabolized in living body.

Meanwhile, as the compounds resembling the compound of the presentinvention, there are known several nucleosides having the chemicalstructure in which a methylene group is inserted between the nucleicacid base moiety and the sugar one. They are generally calledhomonucleosides. For example,2,5-anhydro-1-doexy-1-(adenin-9-yl)-D-allitol (1-homoadenosine:Collection Czechoslov. Chem. Commun., 36, 3043 (1971) and J. Heterocycl.Chem., 7, 443 (1970)), 2,5-anhydro-1-deoxy-1-(uracil-1-yl)-D-allitol(1-homouridine: Collection Czechoslov. Chem. Commun., 34, 1684 (1969)and Collection Czechoslov. Chem. Commun., 35, 81 (1970)),2,5-anhydro-1-deoxy-1-(cytosin-1-yl)-D-allitol (1-homocytidine:Collection Czechoslov. Chem. Commun., 34, 1684 (1969)),2,5-anhydro-1,3,4-trideoxy-1-(6-mercaptopurin-9-yl)-D-allitol, and2,5-anhydro-1,3,4-trideoxy-1-(6-methylthiopurin-9-yl)-D-allitol (J. Med.Chem., 15, 571 (1972)) are known. However, useful pharmacologicactivities of these compounds are not disclosed at all. Quite recently,a nucleoside containing an oxetanocin ring suggested its possibility asan antiviral and anticancer agent has been reported (Japanese Laid-OpenH. 5-271224).

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide, as a medicine, ahomonucleoside derivative which is difficult to be subjected to acid andalkali hydrolysis, and is chemically and enzymologically stable byinserting a methylene group between the nucleic acid base moiety and thesugar one of a nucleoside derivative.

The inventors of the present invention have researched in earnest andhave found that a compound of the following general formula I! meet theabove-mentioned object and then have completed the present invention.##STR2## wherein B represents adenin-9-ylmethyl, guanin-9-ylmethyl,hypoxanthin-9-ylmethyl, thymin-1-ylmethyl, uracil-1-ylmethyl, orcytosin-1-ylmethyl; X and Y may be the same or different and eachrepresents hydrogen or hydroxy, with the exception of the case in whichX is hydrogen and Y is hydroxy.

The feature of the present invention exists in the very structure of thecompound of general formula I3. The compound of the present invention isa novel compound not heretofore described in the literature.

Moreover, as above-mentioned, owing to its enhanced stability, bothchemically and enzymologically, the compound of the invention isdifficult to be metabolized in living body, so that its pharmacologiceffect is increased in both intensity and duration as compared with theconventional nucleosides.

The compound of the present invention has antiviral andantimalignant-tumoral activities and has good stability and safety inliving body and, therefore, is useful as a drug.

The compound of the present invention includes the following specificcompounds in addition to the compounds mentioned in working examples forproduction presented later. These compounds are mentioned as an exampleto show a part of the compound of the present invention. The compound ofthe present invention is not limited to these compounds.

2,5-Anhydro-1,3,4-trideoxy-1-(guanin-9-yl) -D-allitol,

2,5-arthydro-1,3,4-trideoxy-1-(uraci-1-1-yl) -D-allitol,

2,5-anhydro-1,3,4-trideoxy-1-(cytosin-1-yl)-D-allitol,

2,5-anhydro-1-deoxy-1-(guanin-9-yl) -D-sorbitol,

2,5-anhydro-1-deoxy-1-(hypoxanthin-9-yl) -D-sorbitol,

2,5-anhydro-1-deoxy-1-(thymin-1-yl)-D-sorbitol,

2,5-anhydro-1,3-dideoxy-1-(guanin-9-yl)-D-allitol,

2,5-anhydro-1,3-dideoxy-1-(hypoxanthin-9-yl) -D-allitol,

2,5-anhydro-1,3-dideoxy-1-(cytosin-1-yl)-D-allitol and

2,5-anhydro-1,3-dideoxy-1-(uracil-1-1-yl)-D-allitol.

The compound of the present invention can be produced, for example, bythe following production processes. Such production processes are nowexplained corresponding to the three classes of compounds according tothe kinds of X and Y in general formula I!.

1. Production of dideoxy compounds (X=hydrogen, Y=hydrogen)

The compound Ia! that is the compound I! wherein X is hydrogen and Y ishydrogen, can be produced, for example, in accordance with the followingreact ion schema. ##STR3## wherein B has the same meaning as definedhereinbefore.

Thus, compound III! is subjected to dehydroxylation reaction to givecompound IV!, which is then reduced to compound Ia!.

The reaction from compound III! to compound IV! can be carried out inaccordance with the method described in the literature (J. Org. Chem.,54, 4780-4785, 1989), as follows.

In a solvent such as acetonitrile, N,N-dimethylformamide (DMF), ordioxane, compound III! is reacted with an acyloxyisobutyryl halide suchas 2-acetoxyisobutyryl bromide at a temperature between the roomtemperature and the reflux temperature for 1-2 hours. While the reactiontemperature depends on the base of compound III!, a temperature aroundroom temperature is preferred for a purine base and the refluxtemperature is preferred for a pyrimidine base.

The resulting reaction product is then dissolved in a suitable solventand treated with several molar equivalents of Zn (Cu) couple reagent,chromous acetate, zinc/acetic acid, or the like for about 0.5-1 hour.The solvent to be used is preferably a polar solvent such as mixedsolvent of methylene chloride and methanol, DMF, acetonitrile, dioxane,etc.

The obtained compound is then treated with a lower alcohol such asmethanol, and concentrated aqueous ammonia at room temperature for 5-24hours, whereby compound IV! can be produced.

Compound IV! is subjected to catalytic reduction in a lower alcoholsolvent such as methanol or ethanol, in the presence of a hydrogenationcatalyst such as palladium chloride, platinum oxide, palladium black or5% or 10% palladium-on-carbon and at room temperature for 2-10 hours,whereby compound Ia! can be produced.

2. Production of arabino compounds (X-hydroxy, Y=hydroxy)

(1) In the case of a purine base

The compound Ib! that is the compound I! wherein X represents hydroxyand Y represents hydroxy and whose nucleic acid base is a purine base,can be produced, for example, by the reactions illustrated in thefollowing schema. ##STR4##

wherein B¹ represents adenin-9-ylmethyl or guanin-9-ylmethyl; B¹¹represents B¹ wherein protected by a nucleic acid base-protective groupwhich is conventionally used in nucleic acid synthesis (e.g. benzoylatedor isobutyrylated B¹); Z represents tetraisopropyldisi loxane-1, 3-diyl.

Thus, compound Ib! can be produced by protecting the nucleic acid baseand sugar moleties of compound IIIa! (compound III! whose nucleic acidbase is a purine base) to give a cyclic compound VI!, then introducingan electron-withdrawing group such as trifluoromethanesulfonyl ormethanesulfonyl, into the 2'-position of this compound VI!, and carryingout a nucleophilic substitution reaction to give compound VII!, anddeprotecting the compound VII!.

Protection of the amino group of the base moiety of compound IlIa! canbe carried out by the method described in literatures (benzoyl foradenine: J. Am. Chem. Soc., 85, 3821 (1963); isobutyryl for guanine: J.Mol. Biol., 72, 251 (1972)) or any method analogous therewith. Then, forprotection of the sugar moiety, the compound is treated with 1-1.2 molarequivalents of 1, 1,3,3-tetraisopropyl-1,3-dichlorodisiloxane at roomtemperature for 1-4 hours to give compound VI!.

In an aprotic solvent such as methylene chloride, and in the presence ofa base such as pyridine, compound VI! is reacted withtrifluoromethanesulfonic anhydride at 0° C. for 0.5-3 hours, whereby theO-trifluoromethanesulfonyl compound can be obtained. This compound isreacted with a nucleophilic reagent such as lithium acetate in a polarsolvent such as DMF, dimethyl sulfoxide (DMSO) orhexamethylphosphoramide (HMPA), at 10°-50° C. for 2-24 hours, wherebythe steric configuration at the reaction site is inverted to givecompound VII! having the substituent group introduced selectively inβ-configuration.

Deprotection of compound VII! can be carried out by known procedures,for example, by treatment with concentrated aqueous ammonia and, then,with a mineral acid such as hydrochloric acid.

(2) In the case of a pyrimidine base

The compound Ic! and the compound Id! that are the compound I!of theinvention wherein X represents hydroxy and Y represents hydroxy andwhose nucleic acid base is a pyrimidine base, can be produced, forexample, by the reactions illustrated in the following schema. ##STR5##wherein Z has the same meaning as defined hereinbefore; R¹ representshydrogen or methyl.

Thus, compound Ic! can be produced by protecting the sugar moiety ofcompound IIIb!, then carrying out a trifluoromethanesulfonylationreaction followed by an intramolecular nucleophilic substitutionreaction to give compound XI!, and deprotecting XI!. Starting withcompound Ic! (R¹ =hydrogen), compound Id! can be produced by the per seknown method.

Protection of the sugar moiety of compound IIIb! can be carried outusing 1,1,3,3-tetraisopropyl-1,3-dichlorodisi loxane in the same manneras described above. The resulting compound is then reacted withtrifluoromethanesulfonic anhydride in an aprotic solvent such asmethylene chloride, in the presence of a base such as pyridine, at 0° C.for 0.5-3 hours to give the O-trifluoromethane-sulfonyl compoundfollowed by an intramolecular nucleophilic substitution reaction of thiscompound at 10°-50° C., preferably at room temperature, whereby compoundXI! can be obtained.

Production of compound Ic! by deprotection of compound XI! can becarried out in the same manner as described hereinbefore.

Production of compound Id! from compound Ic! (R¹ =hydrogen) can becarried out by the method described in a literature (CarbohydrateResearch, 31, 245, 1973) or any method analogous therewith. Thus,compound Id! can be obtained by reacting a compound Ic! (R¹ =hydrogen)with acetic anhydride and pyridine at room temperature to protect thehydroxyl group with acetyl, then reacting the protected compound withphosphorus pentasulfide to give the thiouracil compound, and treatingthe thiouracil compound with ammonia.

3. Production of monodeoxy compounds (X=hydroxy, Y=hydrogen)

The compound Ie!!that is the compound I! of the invention wherein X ishydroxy and Y is hydrogen and whose nucleic acid base is a purine base,can be produced by the reactions illustrated in the following schema.

Process A ##STR6## wherein B¹, B¹¹, and Z have the same meanings asdefined hereinbefore. T represents substituted thiocarbonyl such asimidazolylthiocarbonyl, phenoxythiocarbonyl.

Thus, compound VI! is thiocarbonylated to give compound XIII! which isreduced and then deprotected, whereby compound Ie! can be produced.

Compound XIII! can be produced by reacting compound VI! with athiocarbonyl derivat ive such as N,N'-thiocarbonyldiimidazole or phenylchlorothioformate in a suitable solvent such as anhydrous pyridine at20°-70° C. for 2-10 hours.

Reduction of compound XIII! can be carried out by the known method, forexample using 4-5 equivalents of tributyltin hydride and a catalyticamount of azoisobutyronitrile in a hydrocarbon solvent such as benzeneor toluene at 70°-110° C.

Deprotection of the resulting compound can be carried out by the knownprocedure, for example by treatment with tetrabutylammonium fluoride ora mineral acid such as hydrochloric acid and then with concentratedaqueous ammonia. In this procedure, the order of said treatment withtetrabutylammonium fluoride or a mineral acid such as hydrochloric acidand said treatment with concentrated aqueous ammonia may be reversed.

Process B

(1) In the case of a purine base

The compound Ie! of the present invention can also be produced, forexample, by the reactions illustrated in the following schema. ##STR7##wherein B¹ has the same meaning as defined hereinbefore; R² representshydrogen or amino; Bn represents benzyl.

Thus, compound XVI! can be produced by reacting compound XIV! with an5-amino-4, 6-dichloropyrimidine compound to give a compound XV! andcyclizing compound XV!. Then, after substitution of a suitablesubstituent group (amino for an adenine base; hydroxy for a guaninebase) for the chlorine atom of compound XVI!, catalytic reduction iscarried out, whereby compound Ie! can be produced.

The reaction of compound XIV! with an 5-amino-4,6-dichloropyrimidinecompound can be carried out in the presence of a base such astriethylamine, in a lower alcohol solvent, preferably in n-butanol, at60°-130° C.

The cyclized compound XVI! can be obtained by reacting compound XV! withethyl orthoformate in the presence of a mineral acid catalyst such ashydrochloric acid, at room temperature for 5-24 hours.

Compound XVI! is reacted with ammonia in a hermetically sealed reactiontube in the conventional manner to substitute an amino group for thechlorine atom, whereby the compound whose nucleic acid base is adeninecan be produced. Moreover, by subjecting compound XVI! to acid or alkalihydrolysis in the conventional manner, a hydroxyl group is substitutedfor the chlorine atom, whereby the compound whose nucleic acid base isguanine can be produced.

Compound Ie! can be produced by subjecting the resulting compound tocatalytic reduction in the presence of a catalyst such as palladiumchloride or 5% or 10% palladium-on-carbon, in a lower alcohol solventsuch as methanol or ethanol at room temperature for 0.5-4 hours.

(2) In the case of a pyrimidine base

The compound If! that is the compound I! of the invention wherein Xrepresents hydroxy and Y represents hydrogen and whose nucleic acid baseis a pyrimidine base can be produced, for example, by the reactionsillustrated in the following schema. ##STR8##

In the schema, B² represents uracil-1-ylmethyl or thymin-1-ylmethyl; R³represents hydrogen or methyl; Bn represents benzyl.

Thus, compound If! can be produced by reacting compound XIV! withnitrourea to give compound XVII!, then cyclizing this compound tocompound XVIII!, and subjecting this compound XVIII! to catalyticreduction.

The reaction of compound XIV! with nitrourea can be carried out byheating them together in a solvent mixture of water and a lower alcoholsuch as ethanol at 60°-110° C. for 2-10 hours and then stirring thereaction mixture at room temperature for 5-24 hours.

Compound XVII! is reacted with a suitable reagent(2-methyl-3-methoxypropenoyl chloride or 2-methyl-3-ethoxypropenoylchloride for thymine ring formation or 3-methoxypropenoyl chloride or3-ethoxypropenoyl chloride for uracil ring formation) in the presence ofa base such as pyridine in a solvent such as methylene chloride at roomtemperature for 5-24 hours and, then, reacted with a mixture of aceticacid and concentrated hydrochloric acid at room temperature overnight,whereby the cyclized compound XVIII! can be obtained.

Catalytic reduction of compound XVIII! can be carried out by treatingcompound XVIII! in the presence of a catalyst such as palladium chlorideor 5% or 10% palladium-on-carbon, in a lower alcohol solvent such asmethanol or ethanol, at room temperature for 0.5-4 hours.

The compound I! of the invention wherein B representshypoxanthin-9-ylmethyl can be produced by reacting the correspondingcompound I! wherein B is adenin-9-ylmethyl with sodium nitrite in aceticacid/water at room temperature.

The compound of the invention wherein B is cytosin-1-ylmethyl can beproduced from the compound I! of the invention wherein B isuracil-1-ylmethyl by the method described in the literature(Carbohydrate Research, 31, 245-254, 1973) or any method analogoustherewith.

Compound III! which is used as the starting material for the productionof compound I! of the present invention can be produced by any of themethods disclosed in the above-mentioned literatures describinghomonucleosides and the methods described in the reference examplespresented hereinafter. Moreover, compound XIV! can be produced by themethod described in the reference examples.

Compound III! of the invention wherein B is guanin-9-ylmethyl orthymin-1-ylmethyl is a novel compound not heretofore described in theliterature and is useful as the starting material for the production ofcompound I! of the present invention.

Having potent antiviral activity, the compound of the present inventionis not only expected to act against influenza viruses, hepatitis A, B,and C viruses, labial and genital herpes viruses, herpes simplex 1 and 2viruses in immunosuppressed cases, cytomegarovirus which causes seriouspneumonia in immunosuppressed cases, varicella zoster virus which is apathogenic agent of chickenpox and zona, AIDS virus, etc. but alsoexpected to be a useful therapeutic agent for malignant tumors.

For administration of the compound of the invention as a medicine, itcan be administered to animals inclusive of human being, either as it orin the form of a pharmaceutical composition containing, for example,0.1-99.5%, preferably 0.5-90% of the compound in a pharmaceuticallyacceptable, nontoxic and inert carrier.

As the carrier, one or more formulation auxiliaries such as solid,semisolid and liquid diluents, fillers, and other auxiliary agents canbe selectively employed. The pharmaceutical composition is preferablyadministered in a unit dosage form. The pharmaceutical composition ofthe present invention can be administered intravenously, orally, intothe target tissue, locally (transdermal delivery) or rectally. Ofcourse, the dosage form suited to each route of administration should beused. The oral route is particularly preferred.

The dosage as an antiviral or antimalignant-tumoral drug is preferablyselected with reference to patient conditions such as age and bodyweight, route of administration, nature and severity of illness, andother factors. Usually, for adults, the daily dose of 50-600 mg/man,preferably 100-300 mg/man, in terms of the active ingredient compound ofthe invention is general.

Doses lower than the above range may be sufficient in some cases, whilehigher doses may be needed in other cases. Moreover, It is also possibleto give twice or thrice daily by dividing the daily dose in to two orthree.

BEST MODE OF CARRYING OUT THE INVENTION

The following reference and working examples are intended to describethe present invention in further detail.

Reference Example 11-Amino-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

Step 1 1-β-cyano-3,5-di-O-benzyl-2-deoxy-D-ribose

In 30 ml of methylene chloride was dissolved 1.3 g of1-methoxy-3,5-di-O-benzyl-2-deoxy-D-ribose, and then 46.8 μl of asolution of 0.1 equivalent of boron trifluoride-ether complex solutionwas added under ice-cooling. Then, 3.12 ml of trimethylsilyl cyanide wasfurther added and the mixture was stirred at room temperature for 3hours. This reaction mixture was poured in a cold saturated aqueoussolution of sodium hydrogen carbonate and the methylene chloride layerwas washed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedand the residue was purified by silica gel column chromatography (ethylacetate/n-hexane=1/9) to provide 400 mg of the desirable compound and450 mg of 1-α-cyano-3,5-di-O-benzyl-2-deoxy-D-ribose, each as yel lowoily substance.

Step 2 1-Amino-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

In 30 ml of tetrahydrofuran (THF) was dissolved 4.4 g of 1-β-cyano-3,5-di-O-benzyl-2-deoxy-D-ribose and then 1.78 g of borane-dimethylsulfide complex salt was added in small portions under reflux. After 45minutes of refluxing, the reaction mixture was ice-cooled and 54 ml of2N-hydrochloric acid was added. The mixture was then stirred at 50° C.for 1.5 hours and thereafter at room temperature overnight. The reactionmixture was then neutralized with 1N-aqueous sodium hydroxide solutionand extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to provide 4.4 g ofthe desirable compound as pale yellow oily substance.

Reference Example 2 2,5-Anhydro-1-deoxy-1-(thymin-1-yl)-D-allitol

Step 1 1-Ureido-2,5-anhydro-3,4-O-isopropylidene-1-deoxy-D-allitol

A mixture of 818 mg of1-amino-2,5-anhydro-3,4-O-isopropylidene-1-deoxy-D-allitol and 465 mg ofnitrourea was stirred in 3.5 ml of 50% ethanol/water at 90° C. for 5hours. This reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (methylene chloride→7%methanol/methylene chloride) to provide 631 mg of the desirable compoundas a colorless foamy substance.

Step 2 6-O-Acetyl-1-N-(2-methyl-3-methoxypropenoyl)ureido!-2,5-anhydro-3,4-O-isopropylidene-1-deoxy-D-allitol

In 1 ml of pyridine was dissolved 314 mg of1-ureido-2,5-anhydro-3,4-O-isoproopylidene-1-deoxy-D-allitol followed byaddition of 1 ml of acetic anhydride, and the mixture was stirred atroom temperature for 1 hour. This reaction mixture was concentrated andthe residue was subjected to azeotropic dehydration with toluene 3 timesand then dissolved in 8 ml of methylene chloride/pyridine (3/1), and 360mg of 2-methyl-3-methoxypropenoyl chloride was added. This mixture wasstirred at room temperature overnight. The reaction mixture was thenpoured in 5% aqueous monopotassium phosphate solution and extracted withethyl acetate. The organic layer was washed serially with 5% aqueousmonopotassium phosphate solution twice, saturated aqueous sodiumhydrogen carbonate solution once, and water once, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by TLC (5% methanol/methylene chloride) to provide284 mg of the desirable compound as an oily substance.

Step 3 2, 5-Anhydro-1-deoxy-1-(thymin-1-yl)-D-allitol

In a mixture of 0.47 ml of acetic acid and 4.75 ml of concentratedhydrochloric acid, 258 mg of 6-O-acetyl-1-N-(2-methyl-3-methoxypropenoyl)-ureido!-2,5-anhydro-3,4-O-isopropylidene-1-deoxy-D-allitol was added and stirred at roomtemperature overnight. This reaction mixture was concentrated and theresidue was stirred in ethanol (4 ml)/water(8 ml)/0.6N-hydrochloricacid(4 ml) at 100° C. for 30 minutes. The reaction mixture was thenconcentrated and the residue was subjected to azeotropic dehydrationwith toluene 3 times and then stirred in concentrated aqueous ammonia(5ml)/methanol (3.2 ml) overnight. This reaction mixture was concentratedand the residue was purified by ODS column chromatography (water→10%methanol/water) to provide 180 mg of the desirable compound as whitepowder.

UV: λ_(max) (H₂ O, ph=7) 271.2 nm

IR: cm⁻¹ (KBr) 3400, 1682, 1473.8, 1224.9, 1105.3, 1051.3

Reference Example 3 2,5-Anhydro-1-deoxy-1-(guanin-9-yl)-D-allitol

Step 11-Deoxy-1-(2,5-diamino-6-chloro-4-pyrimidinylamino)-2,5-anhydro-3,4-O-isopropylidene-D-allitol

In a mixture of 2 ml of n-butanol and 3 ml of DMF, 340 mg of1-amino-2,5-anhydro-3,4-O-isopropylidene -1-deoxy-D-allitol, 200 mg of2,5-diamino-4,6-dichloropyrimidine and 384 μl of triethylamine werestirred together at 100° C. for 6.5 hours and then at room temperatureovernight. This reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (methylene chloride→3%methanol/methylene chloride) to provide 110 mg of the desirable compoundas brown oily substance.

Step 2 2,5-Anhydro-1-deoxy-1-(guanin-9-yl)-D-allitol

In a mixture of 1.1 ml ethyl orthoformate and 45 μl concentratedhydrochloric acid, 100 mg of1-deoxy-1-(2,5-diamino-6-chloro-4-pyrimidinyl-amino)-2,5-anhydro-3,4-O-isopropylidene-D-allitol was stirred at room temperatureovernight. This reaction mixture was concentrated to dryness and stirredin ethanol(3.2 ml)/water(6.4 ml)/0.6N-hydrochloric acid (3.2 ml) at 100°C. for 30 minutes. The reaction mixture was then neutralized with 20%sodium hydroxide. After addition of 520 mg of sodium hydroxide, themixture was refluxed for 6.5 hours. This reaction mixture wasneutralized with 6N-hydrochloric acid and the residue was purified byODS column chromatography (water→10% methanol/water) to provide 34 mg ofthe desirable compound as white powder.

UV: λ_(max) (H₂ O, pH=7) 252.8 nm

EXAMPLE 1 2,5-Anhydro-1,3,4-trideoxy-1-(adenin-9-yl)-D-allitol

Step 12,5-Arthydro-3,4-didehydro-1,3,4-trideoxy-1-(adenin-9-yl)-D-allitol

In 0.5 ml of acetonitrile was dissolved 28 mg of2,5-anhydro-1-deoxy-1-(adenin-9-yl)-D-allitol followed by addition of 65μl of 2-acetoxyisobutyryl bromide at room temperature. After 1 hour,saturated aqueous sodium hydrogen carbonate solution was added and themixture was partitioned between methylene chloride and water. Theorganic layer was dried over anhydrous sodium sulfate and concentratedto dryness to give a crude product. This product was dissolved in amixture of 0.2 ml of methylene chloride and 0.8 ml of methanol followedby addition of 0.5 ml of a methanolic suspension of Zn (Cu) couplereagent (prepared in accordance with the method described in Org. Chem.,54, 4785-95 (1989)), and then the mixture was stirred at roomtemperature for 30 minutes. After the depletion of the starting materialwas confirmed by microsilica gel TLC (developping solvent: ethylacetate/acetone=5/1), the reaction mixture was filtered through celite.The liltrate was concentrated to dryness and the residue was stirred inmethanol (3.0 ml)/concentrated aqueous ammonia (10 ml) at roomtemperature overnight. The reaction mixture was then concentrated todryness and the residue was purified by open reversed-phase ODSchromatography (gradient elution with 0% methanol/water→30%methanol/water) to provide 20 mg of the desirable compound as whitepowder. m.p. 225°-228° C. (decomp.)

UV: λ_(max) (H₂ O, pH=7) 261.4 nm

FAB-MS: 248 (M+H)⁺

Step 2 2,5-Anhydro-1,3,4-trideoxy-1-(adenin-9-yl)-D-allitol

In 90% ethanol was dissolved 30 mg of2,5-anhydro-3,4-didehydro-1,3,4-trideoxy-1-(adenin-9-yl) -D-allitolfollowed by addit ion of 20 mg of 1076 Pd-C, and then catalyticreduction was carried out at room temperature for 4 hours. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite. The filtrate was concentrated to dryness and pulverized fromacetone/ethanol to provide 29 mg of the desirable compound as whitesolid. m.p. 199°-201° C.

FAB-MS :250 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 261.2 nm

EXAMPLE 2 2, 5-Anhydro-1,3,4-trideoxy-1-(hypoxanthin-9-yl)-D-allitol

To a solution of 15 mg2,5-anhydro-1,3,4-trideoxy-1-(adenin-9-yl)-D-allitol in 2N-acetic acidwas added 1.2 ml of 2196 aqueous sodium nitrite and the mixture wasallowed to stand at room temperature. This reaction mixture was purifiedby open ODS chromatography (gradient elution with 0% methanol/water→20%methanol/water) and pulverized from acetone/ethanol to provide 15.6 mgof the desirable compound as white solid. m.p. 220°-222° C.

FAB-MS: 251 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 250.2 nm

EXAMPLE 3 2,5-Anhydro-1,3,4-trideoxy-1-(thymin-1-yl)-D-allitol

Step 12,5-Anhydro-6-O-acetyl-3,4-didehydro-1,3,4-trideoxy-1-(thymin-1-yl)-D-allitol

In 4.5 ml of acetonitrile was suspended 120 mg of the2,5-anhydro-1-deoxy-1-(thymin-1-yl)-D-allitol obtained in ReferenceExample 2 foliowed by addition of 320 μl of 2-acetoxyisobutyryl bromideat room temperature. In about 2 minutes the reaction mixture becamehomogeneous. This reaction mixture was refluxed at 100° C. for 2 hours,after which it was cooled, cold saturated aqueous solution of sodiumhydrogen carbonate was added into it, and partitioned between methylenechloride and water. The organic layer was dried over anhydrous sodiumsulfate and concentrated to dryness to give a light yellow solid. Thissolid was dissolved in a mixture of 1.2 ml of methylene chloride and 4.8ml of methanol followed by addition of about 2.0 ml of a suspension ofZn (Cu) couple reagent in methanol and then the mixture was stirred atroom temperature for 40 minutes. This reaction mixture was filteredthrough celite and the liltrate was concentrated to dryness. To theresidue was added 30 ml of concentrated aqueous ammonia/methanol (3/1)and the mixture was stirred at room temperature for 3 hours. After thereaction mixture was concentrated to dryness, 10 ml of aceticanhydride/pyridine (1/1) was added at room temperature and after 1 hourthe mixture was concentrated to dryness. The residue was partitionedbetween methylene chloride and water and the organic layer was dried,concentrated to dryness, and purified by TLC (5% methanol/methylenechloride) to provide 95 mg of the desirable compound as white powder.

Step 2 2,5-Anhydro-1,3,4-trideoxy-1-(thymin-1-yl)-D-allitol

To 5 ml of a methanolic solution of 88 mg of2,5-anhydro-6-O-acetyl-3,4-didehydro-1,3,4-trideoxy-1-(thymin-1-yl)-D-allitol was added 5 ml of concentrated aqueousammonia and the mixture was stirred at room temperature overnight. Thisreaction mixture was concentrated to dryness followed by dissolution in15 ml of 90% ethanol. To this solution was added 30 mg of 10% Pd-C andcatalytic reduction was carried out at room temperature for 5 hours.After completion of the reaction, the catalyst was removed by filtrationthrough filter paper and the filtrate was concentrated to dryness. Theresidue was purified by open 0DS chromatography (elution gradient: 0%methanol/water→10% methanol/water) to provide 56 mg of the desirablecompound as white powder. m.p. 133°-135° C.

EI-MS: 240 (M⁺)

UV: λ_(max) (H₂ O, pH=7) 271.4 mn

EXAMPLE 4 2,5-Anhydro-1-deoxy-1-(adenin-9-yl)-D-sorbitol

Step 1 2,5-Anhydro-1-deoxy-1- (N-benzoyladenin-9-yl)-D-allitol

2,5-Anhydro-1-deoxy-1- (adenin-9-yl) -D-allitol (916 mg) was subjectedto azeotropic dehydration with anhydrous pyridine and then suspended in15 ml of anhydrous pyridine. To the suspension was added 2.75 g ofbenzoyl chloride dropwise under ice-cooling. After the mixture wasreacted at room temperature for 2 hours, it was poured into a mixture of114 g of ice, 9 g of sodium hydrogen carbonate and 100 ml of chloroformand extracted with chloroform. The chloroform layer was concentrated andethanol/pyridine was added to the residue. Then, 13 ml of 2N-sodiumhydroxide solution and 13 ml of ethanol were added under water-coolingand the reaction was carried out at room temperature for 30 minutes.This reaction mixture was neutralized by adding about 13 ml of2N-hydrochloric acid under cooling and concentrated under reducedpressure. The residue was washed with ether and the aqueous layer wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (methanol/water) to provide 1.28 gof the desirable compound. m.p. 85°-90° C.

FAB-MS: 386 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 282.0 nm

Step 2 2,5-Anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tretraisopropyldisiloxane-1,3-diyl) -D-alliotol

To a solution of 160 mg of2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-D-allitol in DMF(1 ml) wereadded 113 mg of imidazole and 153 mg of1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane and the mixture wasaliowed to stand at room temperature for 3 hours. After completion ofthe reaction, the reaction mixture was partitioned between methylenechloride and water, and the organic layer was washed with saturatedsodium hydrogen carbonate solution and water. The organic layer wasdried, concentrated to dryness, and purified by TIC (5%methanol/methylene chloride) to provide 182 mg of the desirable compoundas white powder.

Step 32,5-Anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisooproopyldisiloxane-1,3-diyl)-3-O-trifluoromethanesulfonyl-D-allitol

In 3 ml of pyridine/methylene chloride (1/1) was dissolved 113 mg of2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-D-allitol. After the solution was cooled to 0° C.,210 mg of trifluoro-methanesulfonic anhydride was added and the mixturewas stirred for 1 hour. After completion of the reaction, the mixturewas partitioned between methylene chloride and cold water and themethylene chloride layer was dried, concentrated to dryness, andpurified by TLC (5% methanol/methylene chloride and then 2%methanol/methylene chloride) to provide 117 mg of the desirable compoundas white powder. m.p. 107°-109° C.

FAB-MS: 760 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 280.8 nm

Step 42,5-Anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-3-O -acetyl-D-sorbitol

To a solution of 45 mg of2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl) -3-O-trifluoronaethanesulfonyl-D-allitol in DMF (0.9ml) wasadded 39 mg of anhydrous lithium acetate and the mixture was stirred atroom temperature overnight. After completion of the reaction, thereaction mixture was concentrated to dryness and purified by TLC (4%naethanol/methylene chloride) to provide 32 mg of the desirable compoundas white solid.

FAB-MS: 670 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 280.5 nm

Step 5 2,5-Anhydro-1-deoxy-1-(adenin-9-yl)-D-sorbitol

To a solution of 32 mg2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-3-O-acetyl-D-sorbitol in THF(0.5ml) was added 70 μl of asolution of tetrabutylammonium fluoride in THF at room temperature.After 5 minutes, 0.1 ml of 50% pyridine/water was added and the reactionmixture was concentrated to dryness. To the residue were added 3.0 ml ofmethanol and 3.0 ml of concentrated aqueous ammonia and then the mixturewas allowed to stand at room temperature overnight. This reactionmixture was concentrated to dryness and purified by open ODSchronaatography (elution gradient: 0% methanol/water→10% methanol/water)to provide 18.4 mg of the desirable compound as white powder. m.p.260°-263° C.

EI-MS: 281 (M⁺)

UV: λ_(max) (H₂ O, pH=7) 261.2 nm

EXAMPLE 5 2, 5-Anhydro-1-deoxy-1-(uracil-1-yl)-D-sorbitol

Step 12,5-Anhydro-1-deoxy-1-(uracil-1-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-D-allitol

Using 516 mg of 2,5-anhydro-1-deoxy-1-(uracil-1-yl)-D-allitol, the sameprocedure as Example 4, Step 2 was carried out to provide 760 mg of thedesirable compound as white solid.

FAB-MS: 501 (M+H)⁺

Step 22,5-Anhydro-1-deoxy-(uracil-1'-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-2',3-anhydro-D-sorbitol

In 3.6 ml of pyridine/water (1/1) was dissolved 150 mg of2,5-anhydro-1-deoxy-1-(uracil-1-yl)-4,6-O-(tetraisopropyl-disiloxane-1,3-diyl)-D-allitol, and after thesolution was cooled to 0° C., and then a solution of 169 mgtrifluoro-methanesulfonic anhydride in methylene chloride (0.5ml) wasadded. After 1 hour, the temperature was allowed to rise gradually toroom temperature. After one and half more hours, the reaction mixturewas partitioned between methylene chloride and saturated aqueous sodiumhydrogen carbonate solution, and water in turn. The organic layer wasdried, concentrated to dryness followed by purification by TLC (5%methanol/methylene chloride) to provide 84 mg of the desirable compoundas light brown solid.

FAB-MS: 483 (M+H)⁺

Step 3 2,5-Anhydro-1-deoxy-1-(uracil-1-yl)-D-sorbitol

To a solution of 80 mg of2,5-anhydro-1-deoxy-1-(uracil-1'-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-2',3-anhydro-D-sorbitol in methanol (4.0ml) was added 4.0 ml of0.6N-hydrochloric acid and then the mixture was stirred at roomtemperature overnight. After completion of the reaction, the reactionmixture was concentrated to dryness followed by purification by openreversed phase colurnn chromatography (water) to provide 40 mg of thedesirable compound as white solid. m.p. 183°-184° C.

FAB-MS: 259 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 265.6 nm

EXAMPLE 6 2, 5-Anhydro-1-deoxy-1-(cytosin-1-yl)-D-sorbitol

Step 13,4,6-Tri-O-acetyl-2,5-anhydro-1-deoxy-1-(4-thiouracil-1-yl)-D-sorbitol

The 2,5-anhydro-1-deoxy-(uracil-1-yl)-D-sorbitol (110 mg) obtained inExample 5 was reacted with 2 ml of acetic anhydride and 2 ml of pyridineat room temperature for 1.5 hours and the reaction mixture was thenconcentrated to dryness. The residue was partitioned between methylenechloride and water and the organic layer was dried. The solvent wasevaporated off and the resulting crude product was subjected toazeotropic dehydration with toluene twice and with pyridine twice anddissolved in 8 ml of pyridine. Then, 473 mg of phosphorus pentasulfidewas added thereto and the mixture was refluxed for 2 hours. The reactionmixture was then cooled to room temperature and 0.3 ml of water wasadded. The mixture was stirred at room temperature for 5 minutes. Afterthe most solvent of the reaction mixture was evaporated off, the residuewas partitioned methylene chloride and cold hydrochloric acid, coldsaturated aqueous sodium hydrogen carbonate solution, and water in turn.The organic layer was dried and concentrated to dryness followed bypurification by TIC (3.07% methanol/methylene chloride) to provide 135mg of the desirable compound as yellow solid. m.p. 100°-105° C.

FAB-MS: 401 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 332.6 nm

Step 2 2,5-Anhydro-1-deoxy-1-(cytosin-1-yl)-D-sorbitol

In 30 ml of saturated amonia-methanol was dissolved 120 mg of3,4,6-tri-O-acetyl-2,5-anhydro-1-deoxy-1-(4-thiouracil-1-yl)-D-sorbitoland the reaction was conducted in a hermetically sealed tube at 100° C.overnight. After completion of the reaction, the reaction mixture wasconcentrated to dryness followed by purification by open reversed phasecolumn chromatography to provide 60 mg of the desirable compound aswhite solid. m.p. 230°-232° C.

FAB-MS: 258 (M+H)⁺

UV: λ_(max) (H₂ O, pH=7) 273.0 nm

EXAMPLE 7 2,5-Anhydro-1,3-dideoxy-1-(adenin-9-yl)-D-allitol

Step 12,5-Anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-3-O-(imidazol-1-ylthiocarbonyl)-D-allitol

The 2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-D-allitol (148 mg) obtained in Example 4, Step 2 was subjected toazeotropic dehydration with pyridine twice and dissolved in 2 ml ofanhydrous pyridine. Then, 49 mg of N, N'-thiocarbonyl-diimidazole wasadded and the reaction mixture was heated at 50° C. for 5 hours. Aftercompletion of the reaction, the reaction mixture was concentrated todryness and purified by TLC to provide 150.4 mg of the desirablecompound.

Step 22,5-Anhydro-1,3-dideoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-D-allitol

A solution of 135 ms2,5-anhydro-1-deoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-3-O-(imidazol-1-ylthiocarbonyl)-D-allitol in toluene (3ml)was refluxed and then a solution of 225 mg of tributyltin hydride and 22mg of azoisobutyronitrile in toluene(2ml) was added dropwise over 5minutes. After the mixture was further refluxed for 1.5 hours, it wascooled to room temperature and concentrated to dryness. The residue waspurified by TLC to provide 67 mg of the desirable compound.

Step 3 2,5-Anhydro-1,3-dideoxy-1-(N-benzoyladenin-9-yl)-D-allitol

To a solution of 65 mg of2,5-anhydro-1,3-dideoxy-1-(N-benzoyladenin-9-yl)-4,6-O-(tetraisopropyldisiloxane-1,3-diyl)-D-allitolin THF (0.3ml) was added 0.32 ml of tetrabutylammonium fluoride and themixture was allowed to stand at room temperature for 10 minutes. Aftercompletion of the reaction, the reaction mixture was adjusted to pH 4.0with diluted hydrochloric acid and concentrated to dryness. The residuewas purified by open ODS chromatography (elution gradient: 0%methanol/water→45% methanol/water) to provide 30 mg of the desirablecompound as white solid.

Step 4 2,5-Anhydro-1,3-dideoxy-1-(adenin-9-yl)-D-allitol

To 10 mg of 2,5 -anhydro- 1,3-dideoxy-1-(N-benzoyladenin-9-yl)-D-allitol were added 1 ml of methanoland 0.5 ml of concentrated aqueous ammonia and then the mixture wasallowed to stand at room temperature overnight. The reaction mixture wasthen concentrated to dryness and the residue was tritulated with etherto provide 6.0 mg of the desirable compound as white solid. m.p.227°-230° C.

Elemental analysis (C₁₁ H₁₅ N₅ O₃)

Calcd. (%): C, 49.81; H, 5.70; N, 26.40

Found (%): C, 49.58; H, 5.54; N, 26.18

UV: λ_(max) (MeOH, pH=7) 260.6 nm

EXAMPLE 8 An alternative process for producing 2,5-anhydro-1,3-dideoxy-1-(adenin-9-yl)-D-allitol

Step 1 1-(5-Amino-6-chloropyrimidin-4-yl-amino)-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy -D-allitol

In 48 ml of n-butanol were dissolved 2.5 g of1-amino-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol obtained inReference Example 1, 1.8 g of 5-amino-4,6-dichloropyrimidine, and 1.65ml of triethylamine and then the mixture was stirred at 110° C. for 6hours. This reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (chloroform→1%methanol/chloroform) to provide 2.35 g of the desirable compound asbrown oily substance.

Step 2 2,5-Arthydro-1-(6-chloropurin-9-yl )-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

In 18 ml of ethyl orthoformate was dissolved 2.33 g of1-(5-amino-6-chloropyrimidin-4-yl-amino)-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol followed by additionof 722 μl of concentrated hydrochloric acid and the mixture was stirredat room temperature overnight. The reaction mixture was thenconcentrated and the residue was purified by silica gel columnchromatography (chloroform→1% methanol/chloroform) to provide 1.89 g ofthe desirable compound as pale yellow crystals. m.p. 126°-129° C.

Step 3 2,5-Anhydro-1-(adenin-9-yl)-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

2,5-Arthydro-1-(6-chloropurin-9-yl)-4,6-di-O-benzyl-1,3-dideoxy-D-allitol(1.8 g) was heated in 120 ml of saturated ammonia/methanol at 100° C.overnight. The reaction mixture was then concentrated and the residuewas purified by silica gel column chromatography (1%methanol/chloroform→1.5% methanol/chloroform) to provide 1.42 g of thedesirable compound as pale-yellow crystal s. m.p. 124°-127° C.

Step 4 2,5-Anhydro-1,3-dideoxy-1-(adenin-9yl)-D-allitol

In 50 ml of methanol was suspended 1 g of palladium chloride and thesuspension was stirred in a hydrogen gas stream at atmospherictemperature and pressure for 45 minutes. Then, a solution of 1.2 g of2,5-anhydro-1-(adenin-9-yl)-4,6-di-O-benzyl-1,3-dideoxy-D-allitol inmethanol (50ml) was added and the mixture was further stirred in ahydrogen gas stream at atmospheric pressure and room temperature for 2hours. The reaction mixture was then filtered and the filtrate wasconcentrated. The residue was neutralized with saturated sodium hydrogencarbonate solution followed by purification by ODS column chromatography(0% methanol/water→7% methanol/water) to provide 620 mg of the desirablecompound as white powder. The physical constants of this compound werein complete agreement with those of the compound obtained in Example 7.

EXAMPLE 9 2,5-Anhydro-1,3-dideoxy-1-(thymin-1-yl)-D-allitol

Step 1 1-Ureido-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

1-Amino-2,5-arthydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol (2.4 g)obtained in Reference Example 1 and nitrourea(847 mg) were stirredtogether in 14 ml of 50% ethanol/water at 90° C. for 7 hours and furtherat room temperature overnight. This reaction mixture was concentratedand the residue was purified by silica gel column chromatography(chloroform→1% methanol/chloroform→2% methanol/chloroform) to provide2.3 g of the desirable compound as pale-yellow oily substance.

Step 2 1-N-(2-methyl-3-methoxypropenoyl)ureido!-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol

In 32.2 ml of methylene chloride was dissolved 2.3 g of1-ureido-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol followed byaddit ion of 9.2 ml of pyridine. Then, 1.67 g of2-methyl-3-methoxypropenoyl chloride was added and the mixture wasstirred at room temperature overnight. This reaction mixture was pouredin 5% aqueous solution of monopotassium phosphate followed by extractionwith ethyl acetate. The organic layer was washed with 5% aqueousmonopotassium phosphate solut ion thrice, saturated aqueous sodiumhydrogen carbonate solution once, and saturated aqueous sodium chloridesolution once in turn, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated and the residue was purified bysilica gel column chromatography (chloroform→1% methanol/chloroform) toprovide 2.3 g of the desirable compound as pale-yellow oily substance.

Step 3 2,5-Anhydro-4,6-di-O-benzyl-1,3-dideoxy-1-(thymin-1-yl)-D-allitol

1- N-(2-methyl-3-methoxypropenoyl)ureido!-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol (2.3 g) was stirred in acetic acid (36ml)--concentrated hydrochloric acid (3.6 ml) at room temperatureovernight. This reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (chloroform→1%methanol/chloroform) to provide 1.6 g of the desirable compound aspale-yellow oily substance.

Step 4 2,5-Anhydro-1,3-dideoxy-1-(thymin-1-yl)-D-allitol

In a mixture of 150 ml of methanol and 1 ml of acetic acid weresuspended 1.6 g of2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-1-(thymin-1-yl)-D-allitol and 1g of 10% Pd-C and then the suspension was stirred in a hydrogen gasstream at atmospheric pressure and room temperature overnight. Thereaction mixture was then filtered. The liltrate was concentrated andthe residue was purified by DS column chromatography (0%methanol/water→3% methanol/water) to provide 850 mg of the desirablecompound as white powder. m.p. 111°-114° C.

Elemental analysis (C₁₁ H₁₆ N₂ O₅.H₂ O)

Calcd. (%): C, 48.17; H, 6.61; N, 10.21

Found (%): C, 47.90; H, 6.43; N, 10.22

UV: λ_(max) (MeOH, pH=7) 270.2 nm.

We claim:
 1. A nucleoside derivative of the following general formulaI!: ##STR9## wherein B represents adenin-9-ylmethyl, guanin-9-ylmethyl,hypoxanthin-9-ylmethyl, thymin-1-ylmethyl, uracil-1-ylmethyl, orcytosin-1-ylmethyl; X and Y may be the same or different and eachrepresents hydrogen or hydroxy, exclusive of the case in which X ishydrogen and Y is hydroxy.
 2. A nucleoside derivative of the followinggeneral formula IIIc!: ##STR10## whrein B³ represents guanin-9-ylmethylor thymin-1-ylmethyl.